Despite significant advances in the development of new antiretroviral drugs for the treatment of HIV-1 infection, elimination of HIV-1 latent sanctuaries and the ability to discontinue HAART are not practically feasible since the viral loads rebound upon cessation of treatment. The reservoir of latently-infected, resting CD4+ T cells is extremely long-lived and can persist for decades in patients receiving antiretroviral therapy. The complete elimination of HIV-1 within a patient will therefore likely require novel clinical approaches to purge the reservoir of latently infected cells. We have shown that combinations of pharmacologic agents act synergistically to activate transcription of a broad spectrum of clinically relevant HIV strains. We propose to extend these studies by testing the latency activation potential of small activating RNAs (saRNAs), which are targeted to promoter regions and activate transcription by guiding epigenetic changes in promoter regions. These saRNAs will be tested both as a stand-alone mechanism for latency activation as well as in combination with select pharmacologic agents known to activate latent viral reservoirs. Once viral transcription is activated viral proteins are made, providing selective therapeutic targets fr targeted therapies. We propose to exploit the expression of the HIV-1 envelope protein (gp120) on the surface of infected cells as a target for aptamer mediated delivery of cytotoxic small interfering RNAs (siRNAs) which will selectively eradicate cells harboring actively replicating HIV-1. The proposed approaches are designed to optimize latency activation and subsequently purge patients of their HIV infected reservoirs. We propose to test these novel strategies in cell culture and in a humanized mouse model that supports active and latent HIV-1 infection. If successful, the proposed approaches will create a new paradigm for the eradication of HIV- 1 infection.